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Wednesday, May 25, 2011

Crohn's disease is a chronic inflammatory condition of the gastrointestinal tract causing abdominal pain, diarrhea, GI bleeding, and weight loss. Current therapies for the condition reduce the inflammation but some are expensive and may incur rare but serious side effects, including infections and lymphoma.

Prior research has suggested that endorphins and enkephalins, components of the endogenous opioid system, may play a role in the development or continuation of inflammation. Therefore, researchers at the Pennsylvania State University College of Medicine studied 40 patients with active Crohn's disease to determine possible benefits of naltrexone — an opioid antagonist — in treating the condition [Smith et al. 2011]. In a double-blind, placebo controlled trial patients were randomized to receive either low-dose oral naltrexone (4.5 mg) or placebo daily for 12 weeks. All subjects then continued on naltrexone for an additional 12 weeks.

Writing in an early online edition of the journal Digestive Diseases and Sciences, the researchers reported that 88% of those treated with naltrexone had at least a 70-point decline in Crohn’s Disease Activity Index, or CDAI, scores, compared with only 40% of placebo-treated patients (P=0.009). The CDAI is a scoring system used to quantify symptoms of Crohn's disease and a minimum 70-point reduction on this measure was the primary endpoint.

The secondary endpoint was improvement in gastrointestinal inflammation observed via colonoscopy, with positive response indicated by a 5-point decline from baseline in the Crohn’s Disease Endoscopy Index Severity (CDEIS) score after 12 weeks. On this measure, 78% of subjects treated with naltrexone achieved endoscopic response compared with only 28% of placebo-treated controls (P=0.008). One-third (33%) of those in the naltrexone group achieved remission (CDEIS score <6), whereas only 8% of those on placebo showed the same change; a 25% difference in remission rate.

The researchers had observed no statistical differences between groups at 4 or 8 weeks of treatment, suggesting a favorable response requires at least 12 weeks of therapy. Continued improvements were seen among subjects who continued with or switched from placebo to naltrexone during an additional 12 weeks of therapy. Fatigue was the only side effect reported, and it was significantly greater in subjects receiving placebo.

The researchers concluded that naltrexone improves clinical and inflammatory activity in patients with moderate to severe Crohn’s disease, as compared with placebo-treated controls. “Strategies to alter the endogenous opioid system provide promise for the treatment of Crohn’s disease,” they added.

COMMENTARY: This was a well designed study, funded by the U.S. National Institutes of Health; although, it might have been even more robust had greater numbers of patients been enrolled. Still, it is an expansion and confirmation of an earlier, open-label trial of low-dose naltrexone conducted by this same research group, which had enrolled only 17 patients with Crohn’s disease [Smith et al. 2007]. Overall, 89% of patients in that study exhibited a favorable response to naltrexone therapy, with 67% achieving remission. This was previously acknowledged in our broader evidence-review report on “Opioid Antagonists as Aids for Pain Management” [available here].

The current study exhibited a large effect size for symptom reduction and an NNT=4 for remission at 12 weeks with naltrexone. That is, 1 in 4 patients treated with low-dose naltrexone might achieve remission of Crohn’s disease within about 3 months, as compared with placebo. Hopefully, future trials also will compare naltrexone with other therapies being utilized for this disorder.

In a PharmaLive.com interview [here], lead researcher Jill P. Smith, MD, stated, "Although the cause of Crohn's disease is unknown, research suggests it involves a complex interplay of environmental, genetic, microbial, immune and non-immune factors. We hypothesize that the opioid system is involved in inflammatory bowel disease and that interfering with an opioid receptor will lead to the reversal of the inflammation." The researchers are planning clinical trials to examine low-dose naltrexone in children with Crohn's disease and have secured orphan drug status from the U.S. FDA for use of the drug in that application.

Naltrexone is FDA-approved as a relapse-prevention therapy for alcoholics or opioid-addicted persons in recovery. As a pure opioid-receptor antagonist, naltrexone blocks the effects of opioids taken externally, but its role in helping to prevent alcoholic relapse is less well understood. Naltrexone hydrochloride is a generic product, although there are branded versions (in 50 mg tablets) approved for addiction treatment. Formulation as a low-dose product (eg, 4.5 mg as in the present study) would need to be done “off label” by a custom compounding pharmacy.

Smith and a fellow member of the research team, Ian Zagon, PhD, hold a patent for the use of naltrexone in inflammatory bowel disease — Crohn's disease and ulcerative colitis — according to the PharmaLive.com article. If this is true, the propriety and potential bias of researchers receiving government funding to explore the efficacy of a product for which they hold a patent regarding the clinical application being studied might merit further examination.

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